Linear polyesteramides from aminophenolic esters

ABSTRACT

The present invention is directed to linear, biodegradable polyesteramide (PEA) polymers synthesized with repeating units derived from aminophenol esters and diacids. These PEAs have a monomer repeat represented by 
     
       
         
         
             
             
         
       
     
     as well as a variety of uses to coat, form or comprise medical devices, combination medical devices and pharmaceutical compositions, including sustained release formulations.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/564,736, filed on Sep. 22, 2009, which claims the benefit ofthe filing date of U.S. Provisional Application Ser. No. 61/098,839,filed Sep. 22, 2008, the disclosures of which are hereby incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Current progress in the medical device field is often focused on thecombination product, i.e., devices that have a physical or mechanicalfunction as well as pharmaceutical efficacy. One way to accomplish thisis via the use of nonbiodegradable or biodegradable polymer systems asdrug reservoirs for the combination products. Such polymer systemsbecome the major contact point with tissue and, as such, should bebiocompatible. Additionally, as combination products have become morecomplex, further desirable characteristics have been identified. Forexample, some polymer systems have been designed to be “biobeneficial,”i.e., the polymers purportedly control protein adsorption and celldeposition (U.S. Pat. No. 7,186,789).

Polymers and polymer systems such as these act as the delivery vehiclefor pharmaceutical agents to surrounding tissues and may serve otherpurposes in a combination product, including physical or mechanicalfunctions. Polymeric delivery vehicles in combination products havetaken the form of coatings for stents to deliver drugs (U.S. Pat. Nos.7,056,591; 7,005,137; 6,953,560 and 6,776,796; and U.S. Pat. Appln. Pub.Nos. 2006/0115449 and 2005/0131201), coatings on surgical meshes toincrease handling characteristics and/or for drug delivery (U.S. Pat.Appln. Pub. No. 2007/0198040), coatings for pacemaker pouches tostabilize the tissue pocket and deliver drugs (U.S. Pat. Appln. Pub. No.2008/0132922), drug-eluting sutures (Ming et al., 2007), anddrug-eluting breast implant covers (U.S. Ser. No. 12/058,060, filed Mar.28, 2008).

As medical providers and patients require greater product performance,the demands placed upon the polymer as an active entity have increased.For example, some of the original stent coatings were polymeric filmswrapped around the stent. These films delivered drug directly to thevessel wall by the force of stent expansion with the film being held inplace by the stent itself (U.S. Pat. Nos. 5,634,946 and 5,674,287).Current research in the stent coating field focuses on optimizingpolymer biocompatibility (WO 2007/056134, U.S. Pat. Nos. 5,317,077;5,216,115; and 5,099,060), melt viscosity (U.S. Pat. Appln. Pub. No.2008/0187567), protein adsorption characteristics (U.S. Pat. Appln. Pub.No. 2006/0115449), hydrophilicity, or physicomechanical characteristics(U.S. Pat. Appln. Pub. No. 2005/0131201).

While many polymer classes are known and a variety of those are beingused in combination products, synthetic polymers containing the aminoacid tyrosine confer many advantages and opportunities to optimizepolymer properties. These advantages are partially derived fromtyrosine's inherent biocompatibility, lack of toxicity, aromatic nature,and three potential polymerization sites, i.e. the phenolic hydroxylgroup, the amino group, and the carboxylic acid group.

One of tyrosine's original uses in a synthetic polymer arose from Kohn'sand Langer's work with tyrosine dipeptides wherein an amino-protectedtyrosine was dimerized with a tyrosine ester to form a monomeric,diphenolic compound. That di-tyrosine diphenol was copolymerized withdicyanate to produce tyrosine-based polyiminocarbonates to create newimmunomodulatory agents (U.S. Pat. No. 4,863,735). Subsequently, Kohninvented several polymeric classes of tyrosine-based polymers in which atyrosine ester was dimerized with a des-aminotyrosine (i.e., tyrosinelacking its amino group) to form a “tyrosine-derived diphenol.” Thosediphenols were condensed with reagents containing two active sites toform several different polymeric classes, including “polyarylates”(polyesters) and polycarbonates (e.g., U.S. Pat. Nos. 7,271,234; RE37,795E; RE 37,160E; 5,216,115; 5,099,060), polyiminocarbonates (e.g.,U.S. Pat. No. 4,980,449), polyethers, polythiocarbonates,polyphosphonates (e.g., U.S. Pat. No. 5,912,225) and others. A laterdeveloped group of tyrosine-derived diphenolic polymers, in which thetyrosine side chain ester is converted to a free acid afterpolymerization has been shown to be an extremely versatile,biocompatible family of materials (U.S. Pat. No. 6,120,491).

Tyrosine-derived diphenolic polyarylates are finding application inantimicrobial-eluting combination devices such as hernia repair meshesand pacemaker covers. They have also been used for combinationdrug-device products such as drug-eluting stent coatings, breast implantcovers, and other applications. Tyrosine-derived diphenolicpolycarbonates are being used as fully resorbable cardiovascular stents(Kohn et al., 2005).

Other tyrosine-derived diphenolic polymers have been described byPacetti et al. (U.S. 2006/0115449). These polymers includetyrosine-derived diphenolic polycarbonates and polyiminocarbonates foruse as drug-eluting stent coatings. Pacetti noted that his “tyrosinedipeptide-based bioabsorbable polymers” have mechanical strengthadvantages because the diphenolic moiety increases rigidity and provideshigher glass transition temperatures (Tg). Kohn et al. and Baluca (U.S.Pat. Appln. Pub. Nos. 2008/0187567 and 2008/0112999, respectively)disclosed N-substituted monomers and polymers containingtyrosine-derived diphenols and indicated that protecting the nitrogenappeared to confer a lower glass transition temperature compared to theunprotected species, apparently lowering it enough to conferprocessability to the materials. Moses et al. have disclosedtyrosine-derived diphenolic monomers and polymers with side chain amidesinstead of esters (WO 2007/056134).

When copolymerized with the appropriate components, tyrosine providesassets for resorbable combination medical device products such as lackof toxicity, biocompatibility and rigidity. For example, Kohn'styrosine-derived diphenolic polycarbonates (U.S. Pat. No. 5,198,507) andpolyarylates (U.S. Pat. No. 5,216,115) lend rigidity to a device becauseof their relatively high glass transition temperatures compared topoly-lactic and glycolic acid-based systems. While the glass transitiontemperature in these polymer families can be moderated by increasing thenumber of carbons in the backbone or side chain of the polymer(Brocchini et al., 1997), the resorption times for most of thesepolyarylates are in excess of one year and in excess of 5-10 years forthe corresponding polycarbonates (Tangpasuthadol et al., 2000a;Tangpasuthadol et al., 2000b).

Because these polymers do not generally meet the resorption timerequirements for the bulk of the resorbable medical products, whichrequire resorption times that vary anywhere from several weeks toseveral months (e.g., resorbable PGA or PLGA sutures (Ethicon)) to threeto six months (cardiovascular stent coatings and/or drug deliverysystems (Conor, Biosensors), these polymers are not adequate for manymedical needs. Moreover, long resorption times make regulatory hurdlesprohibitively expensive because biocompatibility at the implant site ofchoice may need to be shown through full resorption. For example, anyproduct with a polymer coating that takes 2 years to resorb will requireat least a 2-year preclinical program followed by a 2-3 year clinicalprogram in advancing towards regulatory approval.

Thus, the polymer resorption time, along with physicomechanicalproperties, biocompatibility and drug elution times will contribute tothe success of a significant number of combination products. While Kohnreduced the resorption time of the tyrosine-derived diphenolicpolyarylates and polycarbonates to a limited extent via the selectiveintroduction of free acid side chains into the diphenolic monomerstructures (U.S. Pat. No. 6,120,491), the introduction of those sidechains significantly increased the complexity and cost of the synthesisof these materials as well as the glass transition temperature (in somecases, out of the range of polymer processability (U.S. Pat. Appln. Pub.No. 2008/0187567). Furthermore, while the addition of free acid sidechains decreased the resorption time for those polymeric fragmentscontaining the free acid side chain, the degradation process still leftlong polymeric fragments containing ester side chains with resorptiontimes equivalent to those of the original polymer that did not containthe free acid (U.S. Pat. No. 6,120,491).

Therefore, the need remains for a biodegradable, biocompatible family ofpolymers with resorption times of less than one year, and preferably fora subset with resorption times of less than 6 months that have anaccompanying drug elution potential as well as glass transitiontemperatures in the useful range of 20-85° C. The present inventionaddresses these shortcomings in the art and more by providing linearpolyesteramides formed from aminophenol esters, e.g., tyrosine estersand the like, and diacids in the manner described herein. Moreover,while the polymers of the instant invention can incorporate both freeacid side chains and esterified side chains, these polymers do notrequire the presence of free acid side chains to provide fast resorptiontimes, making them cheaper and easier to synthesize than the polymersdisclosed in U.S. Pat. No. 6,120,491.

SUMMARY OF THE INVENTION

The present invention is directed to polymers that are biodegradablepolyesteramide (PEA) polymers and, with appropriate selection of thevarious R groups, a substantial number of the polymers are capable ofresorption under physiological conditions in medically relevant timeperiods. Moreover, these properties are achieved via inexpensive andsimple synthetic routes, while providing polymers with the robustmechanical and physical characteristics as well as lack of toxicityassociated with the presence of tyrosine and related aromatics.

Accordingly, the synthetic PEA polymers of the invention compriseaminophenol-diacid repeating units represented by the formula

wherein

R is —(CR₃R₄)_(a)— or —CR₃═CR₄—;

R₁ is hydrogen; saturated or unsaturated alkyl, aryl, alkylaryl or alkylether having from 1 to 20 carbon atoms; or—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆;

each R₂ is independently a divalent, linear or branched, substituted orunsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene,alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms;—R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—;

R₃ and R₄ are each independently, hydrogen or linear or branched,substituted or unsubstituted alkyl having from 1 to 10 carbon atoms,

R₅ is independently linear or branched, lower alkylene or loweralkenylene;

R₆ is independently linear or branched, substituted or unsubstituted,saturated or unsaturated lower alkyl;

the aromatic ring has from zero to four Z₁ substituents, each of whichis independently selected from the group consisting of halide, loweralkyl, alkoxy, nitro, alkyl ether, a protected hydroxyl group, aprotected amino group and a protected carboxylic acid group;

Y is

a is 0 to 10;

each q is independently 1 to 4;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

In particular embodiments, the polymers of the invention comprise fromat least about 0.01% to 100% of the repeating unit and thus includecopolymers and homopolymers.

Another aspect of the invention is directed to polymers of the inventionblended with one or more second polymers. The second polymers are alsobiocompatible but can be biodegradable, resorbable or stable as neededfor the particular use. A nonlimiting list of particularly useful secondpolymers, especially for fully resorbable products, include polyethyleneglycol (PEG), poly(D,L-lactide) (PLA), polyglycolic acid [polyglycolide(PGA)], poly(D,L-lactide-co-glycolide) (PLGA) and diphenol-derived ortyrosine-derived diphenol polyarylates and polyiminocarbonates and thelike. The polymers blends of the invention can further include one ormore drugs and thus include pharmaceutical compositions.

In yet another aspect of the invention, the polymers and/or blends ofthe invention can be formulated into pharmaceutical compositionscomprising one or more drugs, and optionally, one or morepharmaceutically-acceptable carriers to provide formulations withvarying drug release profiles and characteristics. Such drugs include,but are not limited to, antimicrobial agents, anesthetics,anti-inflammatory agents, anti-scarring agents, growth factors,anti-neoplastic agents and anti-fibrotic agents. The pharmaceuticalcompositions include a range of physical formulations, includingmicrospheres, microparticles, rods, pastes, films, creams, tablets orthe like.

In a further aspect, this invention provides medical devices comprisingor formed from one or more of the PEA polymers or polymer blends of theinvention, with or without one or more drugs. The invention furtherincludes medical devices that are coated with one or more of the PEApolymers or polymer blends of the invention, again with or without oneor more drugs. Such devices include but are not limited to, implantableor insertable devices such as stents; surgical meshes; coverings,pouches, pockets, bags and the like that can be used in conjunction withanother device (e.g., pacemakers, difibrillators, neurostimulators,implantable pumps, breast implants); wound closure adjuncts; flat sheetsor films for use alone or in conjunction with another medical device;

and any type of catheter. Coatings as used in the instant invention,when present, can be disposed on any surface of the device as a partialor full coating and can be single- or multi-layered. The coatings caninclude blends with other polymers of the invention or otherbiocompatible polymers, with and without one or more drugs asappropriate to the use or need.

In a still further aspect, the instant invention provides methods ofpreventing, treating or ameliorating a disorder or condition in apatient by implanting a medical device of the invention (with or withoutone or more drugs) in a patient or administering atherapeutically-effective amount of a pharmaceutical composition of theinvention. Implantable or injectable compositions and medical devices ofthe invention can be used to treat or ameliorate a cardiovasculardisorder, a neurological disorder, a hernia or hernia-related disorder,an ophthalmic condition, or to effectuate an anatomical repair,reconstruction, replacement or augmentation of a body part, limb, tissueor organ of a patient, or to stabilize an implantable device, includingpulse generators, defibrillators, implantable pumps, breast implants andthe like. Hence, the methods of the invention can prevent or ameliorate,for example, the morbidities associated with implantation of comparableuntreated medical devices, including scarring, pain and infection.

In a yet still further aspect, the present invention is directed to amethod of synthesizing a strictly alternating PEA polymer by reactingabout two equivalents of an aminophenol and about one equivalent of afirst diacid with a coupling agent for a time and under conditions topreferentially form amide bonds and produce anaminophenol-diamide-aminophenol trimer; recovering the trimer andfurther reacting it with a about one equivalent of a second diacid inthe presence of a second coupling agent for a time and under conditionsto form said PEA polymer and recovering the polymer. This synthesismethod allows one to easily vary the diacids and aminophenols in the PEApolymer in a predictable structural manner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphically illustrates mass retained under physiologicaldegradation conditions for random and alternating polymers onpolymer-coated meshes: (□) TE glutarate alternating; (▪) TE glutaraterandom; () TE diglycolate alternating; (∘) TE diglycolate random.

FIG. 2 graphically illustrates molecular weight retained underphysiological degradation conditions for random and alternating polymerson polymer-coated meshes: (□) TE glutarate alternating; (▪) TE glutaraterandom; (∘) TE diglycolate alternating; () TE diglycolate random.

FIG. 3 graphically illustrates molecular weight retained underphysiological degradation conditions for three different random polymerson polymer-coated meshes: (♦) TE succinate; (▪) TE glutarate; () TEdiglycolate.

FIG. 4 graphically illustrates the cumulative percentage release ofrifampin under physiological conditions from four random polymers onpolymer-coated meshes: (♦) TE succinate; (▪) TE glutarate; () TEdiglycolate; (▴) TE:15T glutarate.

FIG. 5 graphically compares molecular weight loss under physiologicalconditions for a tyrosine-derived diphenol polymer, p(desaminotyrosyltyrosine ethyl ester succinate) (♦) relative to p(TE succinate) (▴). Thepolymer p(desaminotyrosyl tyrosine ethyl ester succinate) is abbreviatedas p(DTE succinate).

FIG. 6 graphically compares the mass loss of p(10% desaminotyrosyltyrosine 90% desaminotyrosyl tyrosine ethyl ester succinate) (♦), p(15%desaminotyrosyl tyrosine 85% desaminotyrosyltyrosine ethyl estersuccinate) (▪), and TE succinate (▴).

FIG. 7 graphically illustrates the release of tirofiban from variouspolymers of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions and Abbreviations

The compounds herein described may have asymmetric centers. All chiral,diastereomeric, and racemic forms are included in the present invention.Geometric isomers of olefins and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention.

By “stable compound” or “stable structure” is meant herein a compound ormolecule that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and for formulation or use.

As used herein, unless otherwise clear from the context, “alkyl” meansboth branched- and straight-chain, saturated aliphatic hydrocarbongroups having the specified number of carbon atoms. Straight and linearare used interchangeably. As used herein “lower alkyl” means an alkylgroup having 1 to 6 carbon atoms. When substituted, the substituents caninclude halide, alkyl, alkoxy, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoroethyl, additional substituents as describedherein, and the like compatible with the synthesis of the molecules ofthe invention.

As used herein, “alkenyl” means hydrocarbon chains of either a straightor branched configuration and which have one or more unsaturatedcarbon-carbon double bonds, such as ethenyl, propenyl, and the like.“Lower alkenyl” is an alkenyl group having 2 to 6 carbon atoms. As usedherein, “alkynyl” means hydrocarbon chains of either a straight orbranched configuration and which have one or more carbon-carbon triplebonds, such as ethynyl, propynyl and the like. “Lower alkynyl” is analkynyl group having 2 to 6 carbon atoms. When the number of carbonatoms is not specified, then alkyl, alkenyl and alkynyl means havingfrom 1-20 carbon atoms. Alkylene, alkenylene, and alkynylene groups arealkyl, alkenyl, and alkynyl groups, respectively, which are divalent.When substituted, the substituents of the alkylene, alkenylene, andalkynylene groups can include halide, lower alkyl, alkoxy, hydroxy,amino, cyano, nitro, trifluoromethyl, trifluoroethyl, additionalsubstituents as described herein, and the like compatible with theproperties and synthesis of the molecules of the invention.

As used herein, “saturated or unsaturated alkyl” refers to any of analkyl group an alkenyl group or an alkynyl group, having any degree ofsaturation, i.e., completely saturated (as in alkyl), one or more doublebonds (as in alkenyl) or one or more triple bonds (as in alkynyl).

Examples of alkyl groups include but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,cyclohexyl, n-heptyl, n-octyl, isooctyl, nonyl, decyl, and the like;alkylene and alkenylene groups include but are not limited to,methylene, ethylene, propylenes, propenylene, butylenes, butadiene,pentene, n-hexene, isohexene, n-heptene, n-octene, isooctene, nonene,decene, and the like. Those of ordinary skill in the art are familiarwith numerous linear and branched hydrocarbon groups. Alkynyl groupsinclude ethynyl and propynyl groups, and alkynylene groups include—C═C—, —C═C—CH₂—, —CH₂—C═C—CH₂—, —CH₂—C═C—CH₂CH₂—, etc.

As used herein, “aryl” means any stable 6- to 14-membered monocyclic,bicyclic or tricyclic ring, containing at least one aromatic carbonring, for example, phenyl, naphthyl, indanyl, tetrahydronaphthyl(tetralinyl) and the like. When substituted, the substituents caninclude halide, alkyl, alkoxy, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoroethyl, or additional substituents as describedherein, and the like compatible with the properties and synthesis of themolecules of the invention. Arylene refers to a divalent aryl group.

As used herein, “alkylaryl” refers to moiety in which an aryl group isattached to an alkyl group, which in turn is the attachment point of thesubstituent to the molecule. For example, a benzyl ester represents analkylaryl moiety in which the methylene attached to a phenyl ring isbonded to the oxygen of the ester in the formula COOR, where R is thebenzyl ester. The aryl group of this moiety can optionally besubstituted in accordance with the definitions herein. In analogy toalkylene, arylene, etc., an alkylarylene is a divalent alkylaryl group.

The term “substituted” as used herein means that one or more hydrogenson the designated atom are replaced with a selection from the indicatedgroups, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound. Unlessotherwise clear from the context, if no substituent is indicated, thevalency is filled with a hydrogen.

The terms “radical,” “group,” “functional group,” and “substituent” canbe used interchangeably in some contexts and can be used together tofurther describe a chemical structure. For example, the term “functionalgroup” can refer to a chemical “group” or “radical,” which is a chemicalstructure variable that can be in-chain, pendant and/or terminal to thechemical structure. A functional group may be substituted.

A “halide” or a “halo” group is a halogen atom, and includes fluoro,chloro, bromo and iodo groups. The term “alkoxy” refers to an alkylgroup having at least one oxygen substituent represented by R—O—.

Abbreviations used herein for naming polymers and the subunits thereofinclude Bn or Bz, benzyl; D, des-aminotyrosine; dg or dlg, diglycolate;E or Et, ethyl; glu, glutarate; M or Me, methyl; P,4-hydroxyphenylglycine; PEG, polyethylene glycol; PPG, polypropyleneoxide; succ, succinate; T, tyrosine; and TE, tyrosine ethyl ester.

Polymer Description:

The present invention is directed to biodegradable PEA polymers. Thesesynthetic polymers comprise one or more repeating units represented bythe formula

wherein

R is —(CR₃R₄)_(a)— or —CR₃═CR₄—;

R₁ is hydrogen; saturated or unsaturated alkyl, aryl, alkylaryl or alkylether having from 1 to 20 carbon atoms; or—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆;

each R₂ is independently a divalent, linear or branched, substituted orunsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene,alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms;—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—;

R₃ and R₄ are independently, hydrogen or linear or branched, substitutedor unsubstituted alkyl having from 1 to carbon atoms,

R₅ is independently linear or branched, lower alkylene or loweralkenylene;

R₆ is independently linear or branched, substituted or unsubstituted,saturated or unsaturated lower alkyl;

the aromatic ring has from zero to four Z₁ substituents, each of whichis independently selected from the group consisting of halide, loweralkyl, alkoxy, nitro, alkyl ether, a protected hydroxyl group, aprotected amino group and a protected carboxylic acid group;

Y is

a is 0 to 10;

each q is independently 1 to 4;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

These polymers are biodegradable PEA polymers having aminophenol unitsand diacid units which can be generally represented by the formulap(-AP-X—)_(n), where n is the actual number or the weight average numberof repeat units in the polymer. The aminophenols (AP) have the structureshown in Formula I

and the diacids (X) have the structure shown in Formula II

When these monomeric units are polymerized under condensation conditions(or other precursors depending on the synthesis route), the resultantpolymers have backbones with both ester and amide bonds, and side chainswith ester or free acids (depending on the choice of R₁). While therepeat motif of the polymer has the structure AP-X, this simplerepresentation of the polymer does not reflect the various couplingpermutations of the aminophenol and the diacid, i.e., whether thecoupling between the aminophenol and the diacid occurs via reaction ofthe AP's amine functional group with one of the acid groups to producean amide linkage or via reaction of the AP's hydroxyl functional groupwith one of the acid groups to produce an ester linkage. Hence, the AP-Xrepeat unit can be represented by the either structure below (“repeat a”or “repeat b”, respectively).

However, this simple structural representation (-AP-X—) does not showthe relative relationship of these units to one another since theseunits can be further joined together by either an amide or ester bond.Hence, the actual structures of the polymers of the present inventionwhich contain the aminophenol and diacid moieties described herein,depend on the choice of synthetic route, the choice of coupling agentsand the selective reactivity in forming amide or ester bonds.

Accordingly, the polymers of the invention are random copolymers ofrepeats a and b or strictly alternating copolymers of repeat a, repeat bor both repeats a and b, with the particular polymer structuredetermined by the method of synthesis as described herein.

For purposes of nomenclature, random copolymers of repeats a and b, aredenominated by the simple formula p(-AP-X—), AP-X or as random abpolymers, such names being used interchangeably. Names for this polymerclass are based on these representations so that random ab polymers arenamed for the aminophenol moiety followed by the diacid moiety,regardless of the starting materials. For example, a polymer made byrandom copolymerization of tyrosine ethyl ester (TE) as the aminophenolmoiety with succinic acid as the diacid moiety is referred to as p(TEsuccinate) or TE succinate. If the diacid moiety were changed toglutaric acid, this random copolymer would be p(TE glutarate) or TEglutarate. For additional clarity or emphasis, the word random may beappended to the polymer name, e.g., TE succinate random or p(TEsuccinate) random. If the polymer is designated without anything afterthe name, then the polymer is a random copolymer.

There are two strictly alternating copolymers classes that can beobtained from these monomeric units: (1) a linear string of a singlerepeat, either “repeat a,” thus in format (a), or “repeat b,” thus informat (b)_(n), which are equivalent formats; or (2) a linear string ofalternating “repeat a” and “repeat b,” thus in form (ab)_(n) or(ba)_(n), which are equivalent representations for these polymers. Inall cases, n is the number of repeat units. For polymers, n is usuallycalculated from the average molecular weight of the polymer divided bythe molecular weight of the repeat unit.

For purposes of nomenclature, strictly alternating polymers of the (a),form are referred to as p(—O-AP-X—) or as alternating “a” polymers.Alternating “a” polymers occur when the reaction conditions are suchthat the free amine of the aminophenol reacts first with the diacid (orother appropriate reagent) as controlled by the reaction condition,forming an amide linkage and leaving the hydroxyl free for furtherreaction. For example, a polymer made by copolymerization of tyrosineethyl ester (TE) as the aminophenol moiety with succinic anhydride (toprovide the diacid moiety) leads to an alternating “a” polymer and isreferred to herein as p(O-TE succinate) or O-TE succinate.

For purposes of nomenclature, polymers of the (ab)_(n) form are referredto as p(-AP-X₁-AP-X₂—), p(AP-X₁-AP X₂) or as AP-X₁-AP X₂, when having aand b repeats with different diacids or as “p(-AP-X—) alternating” or asAP-X alternating, when the a and b repeats have the same diacid.

Polymers with two different diacids can be made, for example, byreacting two equivalents of an aminophenol with one equivalent of afirst diacid under conditions that favor amide bond formation andisolating the reaction product, a compound having the structureAP-X₁-AP, which is also referred to herein as a trimer because itconsists of two aminophenol units and one diacid unit. This trimer isreacted with a second diacid under polymerization conditions to producethe polymer p(-AP-X₁-AP-X₂—) if the second diacid is different from thefirst diacid, or to produce the polymer p(-AP-X—) alternating if thesecond diacid is the same as the first diacid. As an illustration, aninitial trimer made from TE and succinic acid is denominated asTE-succinate-TE. Reaction of TE-succinate-TE with glutaric acid producesthe polymer p(TE-succinate-TE glutarate), whereas reaction with succinicacid produces the polymer p(TE succinate) alternating. The polymers ofthe invention also include polymers made with mixed aminophenol repeats,mixed diacid repeats and mixed trimer repeats, or any combination ofsuch mixtures. For these complex polymers, the mixed moiety isdesignated by placing a colon between the names of the two moieties andindicating the percentage of one of the moieties. For example,p(TE:10TBz succinate) random is a polymer made by using a mixture of 90%tyrosine ethyl ester and 10% tyrosine benzyl ester with an equimolaramount of the diacid succinic acid under random synthesis conditions. Anexample of a strictly alternating (ab)_(n) polymer with a mixed seconddiacid is p(TE-diglycolate-TE 10PEG-bis-succinate:adipate). This polymeris made by preparing the TE-diglycolate-TE trimer and copolymerizing itwith a mixture of 10% PEG-bis-succinic acid and 90% adipic acid. Anexample of a strictly alternating (ab)_(n) polymer with mixed trimers isp(TE-succinate-TE:35TE-glutarate-TE succinate). This polymer is made byconducting a separate synthesis for each trimer, mixing the isolatedtrimers in the indicated ratio (65 mol % TE-succinate-TE/35 mole %TE-glutarate-TE) and copolymerizing with an equimolar amount of succinicacid. With such complexity, it is often simpler to list the variouscomponents and relative amounts in a table, especially for strictlyalternating (ab)_(n) polymers. Table 1 provides examples of somestrictly alternating (ab)_(n) polymers. In Table 1, T_(g) is the glasstransition temperature of the polymer after synthesis. Mol. Wt. is theweight average molecular weight (M_(w)) of the polymer after synthesisas determined by gel permeation chromatography.

Examples of polymers of the invention include, but are not limited to,those shown in Table 1 as well as polymers (1) wherein the aminophenolunit in the polymer is provided by a tyrosine ester such as tyrosinemethyl ester, tyrosine ethyl ester, tyrosine benzyl ester, freetyrosine, or a methyl, ethyl, propyl or benzyl ester of4-hydroxyphenylglycine as well as 4-hydroxyphenylglycine, and (2)wherein the diacid unit is succinic acid, glutaric acid, adipic acid,diglycolic acid, dioxaoctanoic acid, a PEG acid or a PEG bis-diacid(e.g., PEG-bis-succinate or PEG-bis-glutarate). For polymers with mixedaminophenol repeats, the polymer contains from about 5 to about 40% orfrom about 10 to about 30% of a first aminophenol repeat with theremainder being the second aminophenol repeat. For polymers with mixeddiacid repeats, the polymer contains from about 10 to about 45% or fromabout to about 40% of a first diacid repeat with the remainder being thesecond diacid repeat. For polymers with mixed trimer repeats, thepolymer contains from about 5 to about 40% or from about 10 to about 30%of a first trimer with the remainder being the second trimer. Polymersmade from any and all of the foregoing possible permutations arecontemplated by the present invention. Additional examples of specificpolymers of the invention include p(TE succinate), p(TE succinate)alternating, p(TE glutarate), p(TE glutarate) alternating, p(TEdiglycolate), p(TE diglycolate) alternating, p(TE:15T glutarate), Tg 78,Mol wt. 74 kDa; and p(TE:15TBz glutarate). This last polymer is anexample of an intermediate polymer used in preparation of p(TE:15Tglutarate); i.e., the benzyl ester of TBz is converted to the freecarboxylic acid by removing the benzyl group using known methods, forexample by hydrogenation.

Other polymers of the invention include those in which a strictlyalternating polymer has been synthesized with a trimer selected from thegroup consisting of TE-succinate-TE, TE-glutarate-TE, TE-adipate-TE,TE-diglycolate-TE, and TE-X-TE monomers wherein X is comprised of a PEGunit with or without other species, such as a PEG bifunctionalized viacondensation with two equivalents of a diacid such as succinic acid,glutaric acid, adipic acid, diglycolic acid, or others. Any of thesetrimers can be copolymerized with a diacid repeat selected from thegroup of succinic acid, glutaric acid, adipic acid, diglycolic acid,dioxaoctandioic acid, a PEG acid and a PEG bis-diacid (e.g.,PEG-bis-succinate and PEG-bis-glutarate), or any mixture of thesediacids or other diacids.

The glass transition temperatures for some of these polymers areprovided in the Examples. Additionally, the T_(g) for p(TE succinate) is84° C. and the T_(g) for p(TE:15T glutarate) is 78° C.

TABLE 1 Mol. First Trimer % Second Trimer % % Second X₂ % Tg Wt.AP—X₁—AP 1st AP—X₁—AP 2d First X₂ diacid 1st diacid 2d (° C.) (kDa)TE-diglycolate-TE 100 PEG600 Acid 25 Glutaric acid 75 25 111TE-diglycolate-TE 100 PEG400-bis-succinate 25 Glutaric acid 75 29 130TE-succinate-TE 65 TE-(PEG400- 35 Succinic acid 100 32 120bis-succinate)-TE TE-glutarate-TE 100 PEG400-bis-succinate 35 Succinicacid 65 28 190 TE-glutarate-TE 100 PEG400-bis-succinate 35 Glutaric acid65 26 199 TE-glutarate-TE 100 Glutaric acid 100 70 74 TE-diglycolate-TE100 Glutaric acid 100 61 TE-diglycolate-TE 100 PEG600 Acid 25 Glutaricacid 75 25 TE-diglycolate-TE 100 PEG600 Acid 25 Glutaric acid 75 24TE-diglycolate-TE 100 PEG400-bis-succinate 25 Succinic acid 75 31TE-diglycolate-TE 100 PEG400-bis-succinate 25 Glutaric acid 75 29TE-diglycolate-TE 100 PEG400-bis-succinate 25 Adipic acid 75 25TE-succinate-TE 100 Glutaric acid 100 TE-glutarate-TE 100 Succinic acid100 TE-diglycolate-TE 100 Succinic acid 100 72

The polymers of the invention are biocompatible and biodegradable. Abiocompatible polymer is a polymer which is compatible with livingtissue or a living system and is acceptable for use in or by animals orhumans. Thus, a biocompatible polymer does not cause physiological harmto any significant or unacceptable degree. For example, biocompatibilitycan be assessed by showing that a biocompatible polymer does not causeany or any significant amount of inflammation or immunological reactionor is not toxic or injurious to the living tissue or system. Hence, abiocompatible polymer can be ingested, implanted, inserted, injected,placed on or otherwise used in a living subject or tissue withoutuntoward effects.

As used herein, a “biodegradable polymer” is a polymer that hashydrolytically or oxidatively labile bonds or that is susceptible toenzymatic action or other in vivo breakdown process, or any combinationthereof, under physiological conditions. which action leads to thedegradation and/or breakdown, whether partial or complete, of thepolymer. It should be understood that polymers which are biodegradablehave variable resorption times, which can depend, for example, on thenature and size of the breakdown products as well as other factors.

As used herein a “resorbable polymer,” is a polymer (1) with repeatingbackbone units having at least some bonds that are unstable underphysiological conditions, i.e., in the presence of water, enzymes orother cellular processes, the polymer is biodegradable and (2) thepolymer as a whole or its degradation products are capable of beingtaken up and/or assimilated in vivo or under physiological conditions byany mechanism (including by absorption, solubilization, capillaryaction, osmosis, chemical action, enzymatic action, cellular action,dissolution, disintegration, erosion and the like, or any combination ofthese processes) in a subject on a physiologically-relevant time scaleconsonant with the intended biological use of the polymer.

Resorbable polymers contain cleavable backbone bonds, that when broken,produce smaller fragments, which themselves may be polymeric ormonomeric. These smaller fragments are or can be further degraded tobecome water soluble or to a size that can be engulfed by a macrophage,processed by a cell or otherwise removed from the cellular milieu ortissues at the physiological site of use, resulting in complete orsubstantially complete degradation and loss of the polymer (i.e.,resorption) from the original implantation site. Resorption, forexample, can be assessed by measuring mass loss or weight loss of thepolymer under physiological conditions by methods known in the art.

When resorbable polymers become completely or substantially resorbed,then the polymer (but not necessarily the monomeric repeating unitsthereof or smaller polymeric fragments thereof) is no longer present orno longer readily detectable in the subject. For example, if the polymeris a coating on an implanted medical device, the polymer would no longerbe present on or detectable on the device. Of course, partial resorptionmay also be observed, especially if assessed in an early phase of theresorption process. Similarly, if the polymer is formed into a medicaldevice (e.g., suture material, a staple, a device covering, an implant,a plug) or a sustained-release composition (e.g., a drug formulation orvaccine carrier), then the device or composition may no longer bepresent or detectable at the physiological site of use.

The time scale of resorption depends upon the intended use. The polymersof the invention can be manipulated to provide for rapid resorptionunder physiological conditions, e.g., within a few days, to longerperiods, such as weeks or months or years. Medically-relevant timeperiods depend upon the intended use and include, e.g., from 1-30 days,30-180 days and from 1 to 24 months, as well as all time in between suchas 5 days, 1, 2, 3, 4, 5 or 6 weeks, 2, 3, 4, 6 or months and the like.Accordingly, the present invention includes biocompatible, biodegradablepolymers capable of resorption under physiological condition onmedically-relevant time scales, based on appropriate choice of thegroups, R, R₁, R₂ and like.

Hence, the polymers of the invention comprise one or moreaminophenol-diacid repeating units represented by the formula

wherein the variables are defined as above and the group —C(O)—R₂—C(O)—when taken with the nitrogen and oxygen in the backbone, forms the esterand amide bonds of the polyesteramide backbone of the polymer. Theoxygen attached to the aromatic ring can be in the ortho, meta or paraposition relative to the R group on the aromatic ring and is preferablyin the para position.

More specifically, R is —(CR₃R₄)_(a)— or —CR₃═CR₄—, where a is from 0 to10. If a is zero, then R is a bond. Each R₃ and R₄ is independently ahydrogen or a linear or branched lower alkyl group having from 1 to 10carbon atoms. For example, if R₃ and R₄ are both hydrogen and a is 2,then that moiety is ethylene. In particular embodiments, the R groupsinclude, but are not limited to, a bond, methylene, ethylene, propyleneand butylene.

R₁ is hydrogen; saturated or unsaturated alkyl, aryl, aryl esters,alkylaryl or alkyl ether having from 1 to 20 carbon atoms; or—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆, the latter moiety forming alkyleneoxides.

In particular embodiments, the R₁ groups are hydrogen, methyl, ethyl,propyl, butyl (including t-butyl), hexyl, allyl, benzyl, and alkyleneoxides (e.g., PEGs). When R₁ is an aryl ester, then the substituent canbe a paraben, including methyl paraben, ethyl paraben, propyl parabenand the like. Another aryl ester is desaminotyrosyl ester, e.g.,desaminotyrosyl methyl ester, desaminotyrosyl ethyl ester and the like.

When R₁ is an alkylene oxide, that group can be represented by theformula —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆, (with r, q, s, R₃, R₄, R₅ andR₆ as defined herein). These formulas includes polyethylene glycolchains (PEG) such as —CH₂O(CH₂CH₂O)_(s)CH₂— or—CH₂CH₂O(CH₂CH₂O)_(s)CH₂CH₂— and polypropylene glycol (PPG) chains suchas —CH₂CH₂CH₂O(CH₂CH₂CH₂O)_(s)CH₂CH₂CH₂— and the like. Examples ofpoly(alkylene glycols) include, but are not limited to, PEG, PPG,poly(tetramethylene glycol), PLURONIC® polymers and any derivatives,analogs, homologues, congeners, salts, copolymers and combinationsthereof. As is well known, alkylene oxides can be made or arecommercially available in a variety of sizes and combinations. For PEGs,the sizes include PEG 200, PEG 400, PEG 600, PEG 1000 and the like. ForPLURONIC® polymers, the ratio of polyethylene and polypropylene blocksas well as the overall size can be varied. All such variations arecontemplated for use in the present invention.

Overall, the selection of R and R₁ determine the nature of theaminophenol moiety. Preferred aminophenol moieties in the polymers ofthe invention include tyrosine methyl ester (TM), tyrosine ethyl ester(TE), tyrosine benzyl ester (TBz) and tyrosine (T), which are formedwhen R is CH₂ and R₁ is, respectively, methyl, ethyl, benzyl orhydrogen. Another aminophenol moiety for the polymers of the inventionis 4-hydroxyphenyl glycine and its esters, e.g., PE, PM and PBz.

R₂ is independently linear or branched, substituted or unsubstitutedalkylene, alkenylene, alkynylene, arylene, alkylarylene, a divalentalkyl ether or aryl ether moiety having from 1 to 30 carbon atoms;—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q). R₂ forms part of the diacidmoiety, i.e., as —C(O)—R₂—C(O)— linked by two amide bonds, two esterbonds or an amide and an ester bond, depending on the method ofpolymerization.

Hence, R₂ is a divalent hydrocarbon group and can be linear or branched,substituted or unsubstituted. Such groups include alkylene, alkenylene,arylene, alkylarylene moieties having from 1 to 30 carbon atoms as wellas larger divalent alkylene oxide or arylene oxide moieties (based onthe number of repeating units in those groups). As an example, when R₂is a divalent alkylene oxide, that group can be represented by theformula —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—, (with r, q, s, R₃, R₄, R₅and R₆ as defined herein). This moiety includes polyethylene glycolchains (PEG) such as —CH₂O(CH₂CH₂O)_(s)CH₂— or—CH₂CH₂O(CH₂CH₂O)_(s)CH₂CH₂— and polypropylene glycol chains such as—CH₂CH₂CH₂O(CH₂CH₂CH₂O)_(s)CH₂CH₂—CH₂— and the like. For convenience,these chains are referred to as PEG acids (because of the method ofcondensing these moieties). Further, R₂ can be represented by theformula —(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—, which are referred toas PEG-bis-acids. In a specific embodiment, this formula providespolymers which have PEG bis-succinate as the diacid-based moiety. PEGbis-succinate, taken with the carbonyls of the diacid, is represented bythe formula

—C(O)CH₂CH₂C(O)O(CH₂CH₂O)_(s)C(O)CH₂CH₂C(O)—,

where both R₅s are ethylene, and r, R₃ and R₄ together form an ethylenegroup. If the formula is the same except that both R₅s are n-propylene,then the equivalent moiety is PEG bis-glutarate.

In specific embodiments, the diacid moieties formed with R₂ (i.e., asHO—C(O)—R₂—C(O)—OH) include oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid,and sebacic acid, as well as diglycolic acid (where R₂ is —CH₂OCH₂—),dioxaoctanoic acid (R₂ is —CH₂OCH₂CH₂OCH₂—), alkylene oxide derivativessuch as PEG, PEG bis-succinate and the like. In accordance with theinvention, these diacids units have amide or ester backbone bonds whenpolymerized.

R₃ and R₄ are also present in the groups—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)— and(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q), and each R₃ and R₄ isindependently a hydrogen or a linear or branched lower alkyl grouphaving from 1 to 10 carbon atoms. In these functional groups, when R₃and R₄ are both hydrogen and r is 2, then that moiety is ethylene andwhen taken with oxygen forms the repeating ethylene oxide portion ofPEG. When R₃ and R₄ are both hydrogen and r is 3, then taken with theoxygen they form the propylene oxide repeat of PPG. For—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)— and—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(n)CO(R₅)_(q)—, in most embodiments R₃ and R₄are hydrogen and r is 2 or 3.

R₅, is independently a linear or branched lower alkylene or alkenylenegroup. In preferred embodiments, R₅ is methylene, ethylene or propylene.

R₆ is independently linear or branched, substituted or unsubstituted,saturated or unsaturated lower alkyl. In particular embodiments, R₆ ismethyl, ethyl, propyl, butyl (t-butyl, n-butyl, isobutyl) and the like.

In accordance with the invention, the awl ring of the amino phenol canhave from zero to four Z₁ or Z₂ substituents. If the valence of aposition on the aromatic ring is not otherwise filled, then thatposition has a hydrogen atom. Z₁ or Z₂ are each independently selectedfrom the group consisting of a halide, a lower alkyl, an alkoxy, anitro, an alkylether, a protected hydroxyl, a protected amino and aprotected carboxylic acid group.

When at least one of Z₁ or Z₂ is present and is bromine or iodine, thenthe polymer is radioopaque and has the uses described in U.S. Pat. No.6,475,477. For example, use of radioopaque medical devices allowsnon-invasive techniques to monitor the presence and/or disappearance ofthe device, including the biodegradation and resorption of the device(for devices that are fully resorbable). Similarly, radioopaquemicrospheres formed from polymers of the invention may be useful asimaging agents or for drug delivery, and again can be monitored withnon-invasive techniques such as x-ray, CAT scan, and the like.

Such polymers can be prepared from aminophenol moieties that have beenhalogenated prior to polymerization using standard halogenationreactions. While such reactions may tend to have preferred positions forthe halogen atom on the aromatic ring (e.g., ortho), it is contemplatedthat the halogen atom can be at any available position.

Z₁ can also be a protected hydroxyl, protected amine or protectedcarboxylic group. In addition to the uses of the invention, in someinstances, polymers having such protected substituents can be used asintermediates to prepare other polymers of the invention. Protectinggroups for OH, NH₂ and COOH groups are well known in the art and any aresuitable for use in accordance with the invention, provided they arestable and compatible with the synthetic methods used to produce thepolymers of the invention. Because of the bifunctionality of theaminophenol and the diacid, the basic monomeric unit (here arbitrarilydesignated as repeat a), can add either another of repeat a or addrepeat b as the subsequent monomeric unit. Accordingly, the variable Yreflects this and is defined as repeat a with the amide bond (belowleft) or repeat b with the ester bond (below right).

For a random polymer each subsequent Y would be randomly either “repeata” or “repeat b.” For a strictly alternating (a), polymer, Y wouldalways be “repeat a.” For a strictly alternating (ab)_(n), polymer, Ywould always be “repeat b.” In addition, each R₂ can be the same ordifferent, depending upon the type of polymer and the number ofdifferent diacid monomers employed.

The value of each a is independently 0 or one of the whole numbers 1-10.When a is zero, the corresponding group is omitted and a single carbonbond is present. The value of each q and r is independently one of thewhole numbers 1, 2, 3 or 4.

The value of each s is independently about 1 to about 5000 anddetermines the number of repeat units in the alkylene oxide chain.Hence, s can range from 1 or from 5 to about 10, to about 15, to about20, to about 30, to about 40, to about 50, to about 75, to about 100, toabout 200, to about 300, to about 500, to about 1000, to about 1500, toabout 2000, to about 2500, to about 3000, to about 4000 and to about5000. Additionally, when the length of the alkylene oxide chain isstated as a molecular weight, such as with PEG 200, PEG 400, PEG 600 andthe like, then s need not be a whole number but can also be expressed asa fractional value, representative of the average number of alkyleneoxide repeating units based on the cited (or a measured) molecularweight of the poly(alkylene oxide).

Thus, in one embodiment, the polymers of the present invention includepolymers of structure A:

wherein Z₁ is H, R is —CH₂—, R₁ is a lower alkyl, and Y is:

wherein R₂ and R₂′ are the same; R′ is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁′is hydrogen, lower alkyl, or benzyl; Z₁′ is halide, lower alkyl, alkoxy,nitro, alkyl ether, a protected hydroxyl group, a protected amino groupor a protected carboxylic acid group; and R₂′ is a divalent, linear orbranched, substituted or unsubstituted alkylene, alkenylene, alkynylene,arylene, alkylarylene, alkyl ether or aryl ether moiety having from 1 to30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(n)CO(R₅)_(q)—.

In another embodiment, the polymers of the present invention includepolymers of structure A:

wherein Z₁ is H, R is —CH₂—, R is a lower alkyl, and Y is:

wherein R₂ and R₂′ are different; R′ is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁′is hydrogen, lower alkyl, or benzyl; Z₁′ is halide, lower alkyl, alkoxy,nitro, alkyl ether, a protected hydroxyl group, a protected amino groupor a protected carboxylic acid group; and R₂′ is a divalent, linear orbranched, substituted or unsubstituted alkylene, alkenylene, alkynylene,arylene, alkylarylene, alkyl ether or aryl ether moiety having from 1 to30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

In another embodiment, the polymers of the present invention includepolymers of structure A

wherein Z₁ is H, R is —CH₂—, R is a lower alkyl, and Y is:

wherein R₂ and R₂′ are the same; R′ is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁′is hydrogen, lower alkyl, or benzyl; Z₁′ is halide, lower alkyl, alkoxy,nitro, alkyl ether, a protected hydroxyl group, a protected amino groupor a protected carboxylic acid group; and R₂′ is a divalent, linear orbranched, substituted or unsubstituted alkylene, alkenylene, alkynylene,arylene, alkylarylene, alkyl ether or aryl ether moiety having from 1 to30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

In another embodiment, the polymers of the present invention includepolymers of structure A:

wherein Z₁ is H, R is —CH₂—, R₁ is a lower alkyl, and Y is:

wherein R₂ and R₂′ are different; R′ is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁′is hydrogen, lower alkyl, or benzyl; Z₁′ is halide, lower alkyl, alkoxy,nitro, alkyl ether, a protected hydroxyl group, a protected amino groupor a protected carboxylic acid group; and R₂′ is a divalent, linear orbranched, substituted or unsubstituted alkylene, alkenylene, alkynylene,arylene, alkylarylene, alkyl ether or aryl ether moiety having from 1 to30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

In still other embodiments, the polymers of the present inventioninclude polymers of structure A:

wherein Z₁ is H, R is —CH₂—, R is a lower alkyl, and Y is:

wherein R₂ and R₂′ are the same, and are independently selected from—CH₂—O—CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂—; R′ is —(CR₃R₄)_(a)— or —CR₃═CR₄—;R₁′ is hydrogen, lower alkyl, or benzyl; Z₁′ is halide, lower alkyl,alkoxy, nitro, alkyl ether, a protected hydroxyl group, a protectedamino group or a protected carboxylic acid group; and R₂′ is a divalent,linear or branched, substituted or unsubstituted alkylene, alkenylene,alkynylene, arylene, alkylarylene, alkyl ether or aryl ether moietyhaving from 1 to 30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q);or —(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

In still other embodiments, the polymers of the present inventioninclude polymers of structure A:

wherein Z₁ is H, R is —CH₂—, R is a lower alkyl, and Y is:

wherein R₂ and R₂′ are different, and are independently selected from—CH₂—O—CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂—; R₁′ is hydrogen, lower alkyl, orbenzyl; Z₁′ is halide, lower alkyl, alkoxy, nitro, alkyl ether, aprotected hydroxyl group, a protected amino group or a protectedcarboxylic acid group; and R₂′ is a divalent, linear or branched,substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene,alkylarylene, alkyl ether or aryl ether moiety having from 1 to 30carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or(R₅)_(g)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

In still other embodiments, the polymers of the present inventioninclude polymers of structure A:

wherein Z₁ is H, R is —CH₂—, R₁ is a lower alkyl, and Y is:

wherein R₂ and R₂′ are the same, and are independently selected from—CH₂—O—CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂—; R₁′ is hydrogen, lower alkyl, orbenzyl; Z₁′ is halide, lower alkyl, alkoxy, nitro, alkyl ether, aprotected hydroxyl group, a protected amino group or a protectedcarboxylic acid group; and R₂′ is a divalent, linear or branched,substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene,alkylarylene, alkyl ether or aryl ether moiety having from 1 to 30carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

In still other embodiments, the polymers of the present inventioninclude polymers of structure A:

wherein Z₁ is H, R is —CH₂—, R₁ is a lower alkyl, and Y is:

wherein R₂ and R₂′ are different, and are independently selected from—CH₂—O—CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂—; R₁′ is hydrogen, lower alkyl, orbenzyl; Z₁′ is halide, lower alkyl, alkoxy, nitro, alkyl ether, aprotected hydroxyl group, a protected amino group or a protectedcarboxylic acid group; and R₂′ is a divalent, linear or branched,substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene,alkylarylene, alkyl ether or aryl ether moiety having from 1 to 30carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—.

Examples of particular polymers according to the present invention areshown below, in Table 2:

TABLE 2 Y

TE-diglycolate-TE Z₁ = H Z₁ = H Glutarate R = CH₂ R = CH₂ R₁ = CH₂—CH₃R₁ = CH₂—CH₃ R₂ = CH₂—O—CH₂ R₂ = CH₂—CH₂—CH₂ TE-glutarate- Z₁ = H Z₁ = HTE-glutarate R = CH₂ R = CH₂ R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂ = CH₂—CH₂—CH₂R₂ = CH₂—CH₂—CH₂ TE-succinate- Z₁ = H Z₁ = H TE-glutarate R = CH₂ R =CH₂ R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂ = CH₂CH₂ R₂ = CH₂CH₂—CH₂ TE-glutarate-Z₁ = H Z₁ = H TE-succinate R = CH₂ R = CH₂ R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂= CH₂CH₂—CH₂ R₂ = CH₂CH₂ TE-diglycolate-TE Z₁ = H Z₁ = H (25% peg 600acid/ R = CH₂ R = CH₂ 75% glutaric acid) R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂ =CH₂—O—CH₂ R₂ = CH₂CH₂—CH₂ (75%) = CH₂—O—(CH₂—CH₂—O)₁₀₋₁₂—CH₂ (25%)TE-diglycolate-TE Z₁ = H Z₁ = H (27.5% peg 600 acid/ R = CH₂ R = CH₂72.5% glutaric acid) R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂ = CH₂—O—CH₂ R₂ =CH₂CH₂—CH₂ (72.5%) = CH₂—O—(CH₂—CH₂—O)₁₀₋₁₂—CH₂ (27.5%)TE-diglycolate-TE (25% Z₁ = H Z₁ = H PEG 400 bissuccinate/ R = CH₂ R =CH₂ 75% succinate) R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂ = CH₂—O—CH₂ R₂ = CH₂CH₂(75%) = CH₂—CH₂—COO—(CH₂—CH₂—O)₈₋₁₀—CO—CH₂—CH₂ (25%) TE-diglycolate-TE(25% Z₁ = H Z₁ = H PEG 400 bissuccinate/ R = CH₂ R = CH₂ 75% glutarate)R₁ = CH₂—CH₃ R₁ = CH₂—CH₃ R₂ = CH₂—O—CH₂ R₂ = CH₂CH₂ (75%) =CH₂—CH₂—COO—(CH₂—CH₂—O)₈₋₁₀—CO—CH₂—CH₂ (25%) TE-diglycolate-TE (25% Z₁ =H Z₁ = H PEG 400 bissuccinate/ R = CH₂ R = CH₂ 75% adipate) R₁ = CH₂—CH₃R₁ = CH₂—CH₃ R₂ = CH₂—O—CH₂ R₂ = CH₂CH₂—CH₂ (75%) =CH₂—CH₂—COO—(CH₂—CH₂—O)₈₋₁₀—CO—CH₂—CH₂ (25%) TE-diglycolate-TE (35% Z₁ =H Z₁ = H PEG 400 bissuccinate/ R = CH₂ R = CH₂ 65% adipate) R₁ = CH₂—CH₃R₁ = CH₂—CH₃ R₂ = CH₂—O—CH₂ R₂ = CH₂CH₂—CH₂ (65%) =CH₂—CH₂—COO—(CH₂—CH₂—O)₈₋₁₀—CO—CH₂—CH₂ (35%) TE-15T glutarate Z₁ = H Z₁= H Z₁ = H R = CH₂ R = CH₂ R = CH₂ R₁ = CH₂—CH₃ (85%) R₁ = H (0%) R₁ = H(15%-n) R₂ = CH₂CH₂—CH₂ R₂ = CH₂CH₂—CH₂ R₂ = CH₂CH₂—CH₂

The polymers of the invention can be homopolymers or copolymers. Tocreate heteropolymers (or copolymers), as also described above incontext of polymer nomenclature, mixtures of the aminophenol and/or thediacid (or appropriate starting materials) can be used to synthesize thepolymers of the invention.

When the polymers are copolymers, they contain from at least about 0.01%to 100% of the repeating monomer units, from at least about 0.05, 0.1,0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15% to about 30, 40, 50, 60, 75, 90,95 or 99% in any combination of ranges. In certain embodiments, therange of repeating units in free acid form on the aminophenol moiety ofthe polymer is from about 5 to about 50% (i.e., R₁ is H— prepared via anintermediate in which R₁ is benzyl, and the benzyl is subsequentlyremoved by conventional synthetic methods, e.g., hydrogenolysis), withthe remaining R₁ groups being alkyl or other ester stable tohydrogenolysis. For those polymers, preferred ranges of free acid arefrom about 10 to about 30%, and more preferably from about 10 or about15%.

Alternatively or additionally, the copolymers can have varying ratios ofthe diacid moiety, so that mixtures have from about 20% to about 80% ofat least one diacid described herein, and preferably are mixture of twoor more diacids described herein. Preferred mixed diacids arecombinations of various alkylene oxide type moieties, such as PEG acidsor PEG-bis-alkyl acids or combinations of those alkylene oxide typemoieties with other diacids, especially small, and preferably but notnecessarily, naturally-occurring diacids such as succinic acid, glutaricacid, adipic acid and diglycolic acid. For alkylene oxide mixtures, themixture contains from about 20, 25, 30, 35, 40, 45 to about 50% of onealkylene oxide, and in many embodiments about 50% of each alkyleneoxide. For alkylene oxide-other diacid mixtures, the mixture containsfrom about 20, 25, 30, 35, 40, 45 or 50% of the alkylene oxide, with theremainder being the other diacid. For these combinations, the amount ofthe alkylene oxide in most embodiments is about 20 to about 40%.

Further, the ester moiety of the aminophenol can be varied by usingalkyl esters or another class of esters such as alkylaryl esters, oresters with alkylene oxide chains or ether chains, or another compatiblefunctional group. To have this ester moiety converted to a free acid,the polymer can be synthesized using a benzyl ester (or other easilyhydrolyzable moiety) which can be removed by hydrogenolysis as describedin U.S. Pat. No. 6,120,491 or by other technique that preferentiallyremoves the benzyl group without hydrolyzing the backbone of thepolymer. Hence, the polymers of the invention can be made with mixturesaminophenol and diacids that have variability among the differentsubstituents, i.e., differences can reside at any of R, R₁-R₁₀, Z₁ orthe other variables of the repeat units. Finally, the other monomerunits in the copolymer can be substantially different provided suchmoieties preserve the properties of the polymer and are capable ofcopolymerizing to form polymers with aminophenol and diacid moieties.

Breakdown of the polymers of the invention can be assessed in a varietyof ways using in vitro or in vivo methods known in the art. It may beuseful to mimic the in vivo degradation by in vitro methods. Forexample, aging a polymer-coated device (or a composition or deviceformed primarily from a polymer of the invention) at 37° C. in phosphatebuffered saline (PBS) at pH 7.4 may reproduce the hydrolytic degradationprocess. Mass loss can be assessed in vitro using weight lossmeasurements for pieces of the device, films of polymer or otherrelevant material that have been placed in PBS at 37° C. or in vivo byimplanting materials subcutaneously in a suitable porous container sothat the polymer is exposed to body fluids. Periodic removal of thedevice from the physiological medium or explant container, followed bydrying and weighing produces information related to the mass loss of thematerial. Molecular weight loss can be measured by assessing themolecular weight at predetermined time points from samples explanted,dried, and subjected to GPC to determine the molecular weight. Theidentities of the breakdown products can also be determined by art knowmethods. Further, as needed, in vivo animal models can be used tocorrelate in vivo and in vitro degradation behavior.

Synthesis:

The polymers of the invention can be synthesized by a variety of methodsusing techniques known in the polymer chemistry art. Four methods aredescribed below, but variations of these methods will be within theknowledge of the skilled artisan.

The first of these methods provides strictly alternating (ab)_(n)polymers by synthesizing a trimeric diol and condensing that diol with adiacid to produce the desired polymers. The first step is done underconditions that favor amide bond formation over ester bond formation,for example by using a mild coupling agent such as HOBT(hydroxybenzotriazole). Hence, the monomers are reacted to produce thetrimer

HO-AP-NH₂+HO—C(O)—R_(2a)—C(O)—OH→HO-AP-NH—C(O)—R_(2a)—C(O)—NH-AP-H.

The trimer can also be represented by the structure shown below:

The trimer is purified and reacted with a second diacid,HO—C(O)—R_(2b)—C(O)OH, using a stronger coupling reagent such as DPTS(4-dimethylaminopyridinium 4-toluenesulfonate) to yield the strictlyalternating repeat unit shown below:

[O-AP—NH—C(O)R_(2a)C(O)—NH-AP-O—C(O)—R_(2b)—C(O)]

The second method also produces strictly alternating polymers (ab)_(n)polymers by synthesizing first synthesizing a trimer with protectedamines. This is accomplished by coupling an amine-protected aminophenolwith a diacid, isolating the resultant trimer with protected amines ateach end, deprotecting the amines and reacting with a second diol undercondensation conditions. For example, HO-AP-NHY andHO—C(O)—R_(2a)—C(O)OH are coupled to makeYHN-AP—O—C(O)—R_(2a)—C(O)—O-AP—NHY, where Y is a protecting group thatcan be removed in the presence of the ester bonds in the trimer and APis a shorthand for the remainder of the aminophenol structure other thanthe hydroxyl and amine groups. After deprotection, a second diacid,HO—C(O)—R_(2b)—C(O)OH, is used to polymerize this trimer to form thestrictly alternating (ab)_(n) polymers.

The third method produces strictly alternating (a), polymers by reactingthe aminophenol with an anhydride to produce a dimer with free OH andfree COOH groups as drawn in the exemplary reaction scheme below:

IIO-AP—NII₂+R₂C(O)—O—C(O)—R₂—IIO-AP′NH—C(O)—R₂—OOH.

The reaction product is purified, more coupling reagent added to allowself condensation to proceed and produce a polymer with in which thediacid has an amide bond on one side and an ester bond on the other sideas shown schematically below:

—(—O-AP—NH—C(O)—R₂—C(O)—)(—O-AP—NH—C(O)—R₂—C(O)—)(—O-AP—NH—C(O)—R₂—C(O)—)—.

The fourth synthesis method produces a random copolymer of theaminophenol and the diacid. In this method, equimolar amounts of eachcompound are reacted in the presence of a coupling reagent, preferably astrongly reactive coupling reagent, and catalyst as described, forexample, in U.S. Pat. Nos. 5,216,115; 5,317,077; 5,587,507; 5,670,602;6,120,491; RE37,160E; and RE37,795E as well as in the literature, otherpatents and patent applications. Those of skill in the art can readilyadapt these procedures to synthesize the polymers of the presentinvention. These polymers generally have low to moderate molecularweights (30-60 kDa).

The polymers and synthetic intermediates can be purified by those ofskill in the art using routine methods, including extraction,precipitation, filtering, recrystallization and the like.

Examples of coupling agents for the methods described above include, butare not limited to, EDCI.HCl(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), DCC(dicyclohexylcarbodiimide), DIPC (diisopropylcarbodiimide) incombination with DPTS, PPTS (pyridinium tosylate), DMAP(4-dimethylaminopyridine). The use of EDCI.HCl is preferred forproducing the trimer in the first step for the first synthesis methoddescribed above. Suitable solvents include, but are not limited tomethylene chloride, chloroform, 1,2-dichloroethane, either neat or incombination with lesser quantities of NMP or DMF.

Accordingly, the first method of synthesis described above, provides amethod of the invention directed to a method of synthesizing a strictlyalternating PEA polymer that is at least 40-100% higher in molecularweight than the corresponding random polymer by reacting about twoequivalents of an aminophenol and about one equivalent of a first diacidwith a coupling agent for a time and under conditions to preferentiallyform amide bonds and produce an aminophenol-diamide-aminophenol trimer;recovering the trimer and further reacting it with a about oneequivalent of a second diacid in the presence of a second coupling agentfor a time and under conditions to form said PEA polymer and recoveringthe polymer. This synthesis method allows one to easily vary the diacidsand aminophenols in the PEA polymer in a predictable structural manner.

In this method, the first coupling reaction is conducted underconditions to favor amide bond formation. Such conditions employ mildcoupling conditions and use weaker coupling reagents. A particularlyuseful coupling reagent for this step is EDCI.HCl with the co-catalystHOBt in organic solvent. Reaction times should be chosen to allow thereaction to near or go to completion, i.e., until no or little furthermolecular weight gain appears in the polymer. Typical reaction timesvary from at least overnight (12-16 h) to about (24 to 48 h) and can bereadily determined by those of skill in the art. Reaction temperaturescan also be readily determined by those of skill in the art. In thesecond coupling reaction (after isolation of the trimer), a strongercoupling agent is used to drive ester bond formation. In some cases,after the reaction has proceeded for a time, the second reactionachieves additional molecular weights gains by spiking the reaction witha small additional amount (1-10%) of the second diacid.

In this method the first and second diacids can be the same ordifferent, and either diacid can comprise a mixture of two or moredifferent diacids. Similarly, mixtures of the trimer can be used.Examples of useful coupling agents and solvents are described above andin the Examples.

Uses:

The polymers of the invention have a myriad of biological uses when abiocompatible, biodegradable polymer is needed, for coating medicaldevices, to form fully or partially resorbable medical devices, todeliver drugs in specific manners (either in conjunction with suchdevice or as part of a pharmaceutical composition comprising thepolymer, a drug and other agents. It should be understood that thepolymers are useful without the presence of drugs. For example, apolymer coating on a surgical mesh can increase mesh stiffness, andthereby allow easier handling at the time of implantation yet stillprovide a mesh that softens over time and is comfortable for thepatient. Moreover, a polymer-coated, flat mesh can be formed into athree dimensional shape, and this can be useful in surgical repairs.Fully resorbable devices can be used as sutures intended to impartstrength for a period before dissolving, as temporary wound closures,such as a femoral plug, and the like.

Further uses for the polymers of the invention are described in detail,for example, in U.S. Ser. No. 11/672,929, filed Feb. 8, 2007 whichdescribes coated surgical meshes for a variety of applications; in U.S.Ser. No. 60/864,597, filed Nov. 6, 2006 which describes fully andpartially resorbable coverings, pouches, bags and coated meshes forcardiac rhythm management devices, neurostimulators as well as for otherimplantable medical devices; and in U.S. Ser. No. 60/908,960, filed Mar.29, 2007 for resorbable coverings for breast implants.

The compositions of the present invention can be used to form medicalarticles and coatings (i) that have sufficient mechanical properties forapplications that can benefit from biodegradable polymers, (ii) that canrelease agents substantially free of additional molecules derived from apolymeric carrier, (iii) that can be designed to have a predeterminedrelease rate and resorption rate; and (iv) that can be combined withdrugs that are not only bioactive and/or biobeneficial but also controla physical property and/or a mechanical property of a medical article orcoating formed from the polymer.

Blends:

An additional way to manipulate drug release and resorptioncharacteristics is to blend polymers. Accordingly, the present inventionprovides blends of the polymers of the invention with otherbiocompatible polymers, for example other biodegradable polymers. Theseother polymers include, but are not limited to, polylactic acid,polyglycolic acid and copolymers and mixtures thereof such aspoly(L-lactide) (PLLA), poly(D,L-lactide) (PLA,)polyglycolic acid[polyglycolide (PGA)], poly(L-lactide-co-D,L-lactide) (PLLA/PLA),poly(L-lactide-co-glycolide) (PLLA/PGA), poly(D, L-lactide-co-glycolide)(PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),poly(D,L-lactide-co-caprolactone) (PLA/PCL) andpoly(glycolide-co-caprolactone) (PGA/PCL); poly(oxa)esters, polyethyleneoxide (PEO), polydioxanone (PDS), polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone (PCL), polycaprolactone co-butylacrylate,polyhydroxybutyrate (PHBT) and copolymers of polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates,poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), other tyrosine-derived polyarylates,other tyrosine-derived polycarbonates, other tyrosine-derivedpolyiminocarbonates, other tyrosine-derived polyphosphonates,polyethylene oxide, polyethylene glycol, polyalkylene oxides,hydroxypropylmethylcellulose, polysaccharides such as hyaluronic acid,chitosan and regenerate cellulose, and proteins such as gelatin andcollagen, and mixtures and copolymers thereof, among others as well asPEG derivatives or blends of any of the foregoing.

Using blends provides many advantages, including the ability to makepartially resorbable devices and fully resorbable devices that havevaried resorption times for parts or all of the device. For example, apartially resorbable device may increase porosity over time and thuspermit tissue in growth. Those of skill in the art can readily pickcombinations of polymers to blend and determine the amounts of eachpolymer need in the blend to produce a particular product or achieve aparticular result.

Drugs:

In most embodiments, one or more drug, biological agent, or activeingredient that is compatible with the polymers, monomers and blends ofthe invention can be incorporated in, formed into or used in conjunctionor combination with a pharmaceutical composition or a medical devicecoated or formed from the polymers, monomers or blends of the invention(“compatible” means that the drug does not degrade the polymer, and thepolymer does not degrade the drug). Doses for such drugs and agents areknown in the art and are used in therapeutically-effective amounts. Inaddition to measuring polymer degradation and resorption, those of skillin the art can monitor drug release using the same techniques as well asothers. For example, antibiotic activity can be measured by zone ofinhibition assays, pain relief can be measured in animal models for painand more.

In accordance with the invention, drugs and biologically-active agentsinclude, but are not limited to, anesthetics, antimicrobials (whichinclude antibiotics, antifungal agents and antibacterial agents),anti-inflammatory agents, fibrosis-inhibiting agents, anti-scarringagents, cell growth inhibitors, growth factors and the like.

As used herein, the term “drug” or “drugs” is used to include all typesof therapeutic agents, whether small molecules or large molecules suchas proteins, nucleic acids and the like. The drugs of the invention canbe used alone or in combination.

As used herein, “therapeutically-effective amount” refers to that amountof a drug or bioactive agent necessary to administer to a host toachieve a desired therapeutic effect in treating, ameliorating orpreventing a disease or condition. For example, atherapeutically-effective amount can be that amount to provideantimicrobial activity, pain relief, anti-inflammatory activity,antifibrotic activity, anti-tumor or cancer activity and the likeassociated with the particular drug or biological agent in use.Potentially therepeutically-effective amounts for known drugs areavailable in the literature or can be determined, for new or knowndrugs, using art known methods, techniques and standards.

Examples of non-steroidal anti-inflammatory agents include, but are notlimited to, acetominophen, aspirin, celecoxib, diclofenac, diflunisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamate, meloxicam, methyl salicylate, nabumetone, naproxen,oxaprozin, piroxicam, sulindac, tolmetin and trolamine.

Examples of anesthetics include, but are not limited to, lidocaine,bupivacaine, mepivacaine and xylocalne. Local anesthetics have weakantibacterial properties and can play a dual role in the prevention ofacute pain and infection.

Examples of antimicrobial drugs include, but are not limited toaminoglycosides such as amikacin, gentamicin, kanamycin, neomycin,streptomycin, and tobramycin; antibiotics such as bacitracin,clindamycin, daptomycin, lincomycin, linezolid, metronid, polymyxin,rifaximin, vancomycin; cephalosporins such as cephazolin; macrolideantibiotics such as erythromycin, azithromycin and the like; 13-lactamantibiotics such as penicillins; quinolones such as ciprofloxacin;sulfonamides such as sulfadiazine; tetracyclines such as minocycline andtetracycline; and other antibiotics such as rifampin, triclosan,chlorhexidine, sirolimus and everolimus.

Other drugs that can be used include, but are not limited to, keflex,acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin,daunomycin, plumbagin, atropine, quinine, digoxin, quinidine,biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, nicotinic acid,chemodeoxycholic acid, chlorambucil and anti-neoplastic agents such aspaclitaxel, sirolimus, 5-fluorouracil and the like. Examples of usefulproteins include cell growth inhibitors such as epidermal growth factorantagonists.

Preferred antimicrobial agents of the invention include rifampin,minocycline, gentamicin, vancomycin, triclosan, sirolimus andeverolimus, alone or in combination. Rifampin and minocyline are apreferred combination of anti-microbial agents.

Leukotriene inhibitors/antagonists are anti-inflammatory agents andinclude, but are not limited to, leukotriene receptor antagonists suchas acitazanolast, iralukast, montelukast, pranlukast, verlukast,zafirlukast, and zileuton.

Pharmaceutical Formulations:

The polymers and blends of the invention can be formulated aspharmaceutical compositions comprising one or more of those molecules,one or more drugs (as active ingredient), and a pharmaceuticallyacceptable carrier. Pharmaceutically acceptable carriers can be sterileliquids, such as water and oils, including those of petroleum, animal,vegetable or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil and the like. Water is a preferred carrier when thepharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical carriers are well known. In addition to thepharmacologically active agent, the compositions can contain suitablepharmaceutically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically for delivery to the siteof action. Suitable formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form, forexample, water-soluble salts. In addition, suspensions of the activecompounds, as appropriate in oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides. Aqueous injection suspensionscan contain substances which increase the viscosity of the suspension,which include, for example, sodium carboxymethyl cellulose, sorbitol,and dextran. Optionally, the suspension can also contain stabilizers.Liposomes can also be used to encapsulate the agent for delivery intocells.

The pharmaceutical formulation for systemic administration according tothe invention can be formulated for enteral, parenteral or topicaladministration. Indeed, all three types of formulations can be usedsimultaneously to achieve systemic administration of the activeingredient.

Suitable formulations for oral administration include hard or softgelatin capsules, pills, tablets, including coated tablets, elixirs,suspensions, syrups or inhalations and controlled release forms thereof.

The polymers and blends of the invention can also be incorporated intopharmaceutical compositions which allow for the sustained delivery ofthose compounds to a mammal for a period of several days, to at leastseveral weeks, to a month or more. Such formulations are described inU.S. Pat. Nos. 5,968,895 and 6,180,608 B1.

For topical administration, any common topical formation such as asolution, suspension, gel, ointment or salve and the like can beemployed. The preparation of such topical formulations are welldescribed in the art of pharmaceutical formulations as exemplified, forexample, by Remington's Pharmaceutical Sciences. For topicalapplication, the polymers and blends of the invention can also beadministered as a powder or spray, particularly in aerosol form. Theactive ingredient can be administered in pharmaceutical compositionsadapted for systemic administration. As is known, if a drug is to beadministered systemically, it can be confected as a powder, pill, tabletor the like or as a syrup or elixir for oral administration. Forintravenous, intraperitoneal or infra-lesional administration, theactive ingredient can be prepared as a solution or suspension capable ofbeing administered by injection. In certain cases, it may be useful toformulate the active ingredient in suppository form or as an extendedrelease formulation for deposit under the skin or intramuscularinjection. In a one embodiment, the polymers and blends of the inventionmay facilitate inhalation therapy. For inhalation therapy, the polymersor blends together, with the active ingredient, can be in a solutionuseful for administration by metered dose inhalers or in a form suitablefor a dry powder inhaler.

Medical Devices:

The polymers and blends of the invention can be used to coat or formimplantable prostheses used to reconstruct, reinforce, bridge, replace,repair, support, stabilize, position or strengthen any soft tissuedefect. For example, soft tissue defects that can be treated inaccordance with the instant invention include hernias, including but notlimited to inguinal, femoral, umbilical, abdominal, incisional,intramuscular, diphragmatic, abdomino-throacic and thoracic hernias. Theprosetheses can also be used for structural reinforcement for muscleflaps, to provide vascular integrity, for ligament repair/replacementand for organ support/positioning/repositioning such as done with abladder sling, a breast lift, or an organ bag/wrap. The prosetheses canbe used in recontruction procedures involving soft tissue such as anorthopaedic graft support/stabilization, as supports for reconstructivesurgical grafts and as supports for bone fractures. The prostheses aregenerally meshes, membranes or patches, and include woven or non-wovenmeshes and the like.

Additionally, the polymers and blends of the invention can be used tocoat or to form wound closure adjuncts, such as staples, sutures, tacks,rings, screws, and the like.

The polymers and blends of the invention can also be used to coat mesheswhich are formed into or to form pouches, coverings, pockets and thelike for implantable medical devices. Such implantable medical devicesinclude, but are not limited to cardiac rhythm management devices suchas a pacemaker, a defibrillator, a pulse generator as well as otherimplantable devices such as implantable access systems,neurostimulators, spinal cord stimulators, breast implants or any otherimplantable medical device. The coverings, pouches, pockets and the likehence can serve to secure those devices in position, provide painrelief, inhibit scarring or fibrosis, inhibit or prevent bacterialgrowth or infection, and deliver other drugs to the site ofimplantation.

The polymers and blends of the invention can also be used in conjunctionwith any implantable or insertable medical devices which has atemporary, or some time-limited therapeutic need as well as those withpermanent function (such as joint replacements). For example, suchpolymers can be used to form fully resorbable vascular stents, whichafter a sufficient period of healing become completely resorbed whileleaving a patent blood vessel. Fully resporbable stents may be used inconjunction with one or more drugs.

More detail and other examples of medical devices to which the presentpolymers and blends are useful include, but are not limited to,catheters (e.g., renal or vascular catheters such as balloon catheters),guide wires, balloons, filters (e.g., vena cava filters), stents(including coronary vascular stents, cerebral, urethral, ureteral,biliary, tracheal, gastrointestinal and esophageal stents), stentgrafts, cerebral aneurysm filler coils (including Guglilmi detachablecoils and metal coils), vascular grafts, myocardial plugs, femoralplugs, patches, pacemakers and pacemaker leads, heart valves, vascularvalves, biopsy devices, patches for delivery of therapeutic agent tointact skin and broken skin (including wounds); tissue engineeringscaffolds for cartilage, bone, skin and other in vivo tissueregeneration; sutures, suture anchors, anastomosis clips and rings,tissue staples and ligating clips at surgical sites; orthopedic fixationdevices such as interference screws in the ankle, knee, and hand areas,tacks for ligament attachment and meniscal repair, rods and pins forfracture fixation, screws and plates for craniomaxillofacial repair;dental devices such as void fillers following tooth extraction andguided-tissue-regeneration membrane films following periodontal surgery;and various coated substrates that are implanted or inserted into thebody.

Use of the polymers and blends with any of the medical devices describedherein can include can be used with one or more drugs.

Accordingly, the present invention provides methods of treating adisorder or condition in a patient comprising implanting a medicaldevice or a medical device assembly comprising a polymer or blend of theinvention, e.g., as a coating, in conjunction with a covering or as thecomplete or partial device, by implanting the device in a patient, andparticularly for disorders and conditions such as a cardiovasculardisorder, a neurological disorder, a hernia or hernia-related disorder,an ophthalmic condition, or anatomical repair, reconstruction,replacement or augmentation.

In some embodiments, the method is used to implant a stent to treatatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, or combinations thereof.

In other embodiments, the method is used to implant a surgical mesh toreconstruct, reinforce, bridge, replace, repair, support, stabilize,position or strengthen any soft tissue defect, including a hernia.

In yet other embodiments, the method is used to implant a medical deviceassembly such as a CRM in a covering or pouch, a neurostimulator in apouch or covering, or a breast implant in a pouch or covering.

It will be appreciated by those skilled in the art that variousomissions, additions and modifications may be made to the inventiondescribed above without departing from the scope of the invention, andall such modifications and changes are intended to fall within the scopeof the invention, as defined by the appended claims. All references,patents, patent applications or other documents cited are hereinincorporated by reference in their entirety for all purposes.

Example 1 General Methods

Molecular weight (Mol. Wt.) was determined by gel permeationchromatography (GPC) using 3 cross linked polystyrene columns run inDMF/0.1% TFA at 0.8 ml/m and measured against polyethylene glycolstandards using an R₁ detector.

Tg values were determined by DSC using a heating ramp of 10° C./m.Reported values are computed from a 2^(nd) ramp cycle.

Proton nmr spectra were determined in D₆MSO using tetramethylsilane asan internal calibration standard.

Example 2 Synthesis of Strictly Alternating (Ab)_(n) Polymers

A. Synthesis of p(TE-Dg-TE 35% PEG400-Bis-Succinate:Adipate)

Step 1: Synthesis of TE-Dg-TE

Tyrosine ethyl ester free base (0.256 4 moles; 53.65 g) was reacted withdiglycolic acid (0.1275 moles; 17.1 g) in presence of HOBT.H₂O andEDCI.HCl in N-methylpyrrolidinone (NMP) solvent. The reaction wascarried out at 3-30° C. over a period of 16-18 h. Ethyl acetate was usedduring liquid-liquid extraction purification. Yield: 90%. Melting point:128-129° C. Mass: 517.21 (M+1).

NMR: 9.2-9.25 ppm (2H, singlet;), 8.25-8.32 ppm (2H, doublet), 6.95-7.15ppm (4H, doublet), 6.6-6.7 ppm (4H, doublet), 4.4-4.5 ppm (2H, quartet),4.0-4.01 ppm (4H, quartet), 3.85-3.98 (4H, quartet), 2.82-2.89 ppm (4H,multiplet), 1.08-1.16 ppm (6H, triplet).

Step 2: Synthesis of p(TE-Dg-TE 35% Peg400-Bis-Succinate:Adipate)

TE-Dg-TE (0.1 moles; 51.66 g) was reacted with PEG400-bis-succinic acid(0.035 moles; 22.27 g) and adipic acid (0.065 moles; 9.5 g) in presenceof DPTS and diisopropylcarbodimide (DIPC) in methylene chloride solvent.The reaction was carried out at 32-38° C. over a period of 18-20 h.Isopropyl alcohol was used in precipitation of the polymer. Yield: 88%.GPC: >100 kDa. Tg: 19-22° C.

NMR: 8.37-8.38 ppm (d, 1H), 7.24-7.26 ppm (m, 4H), 6.99-7.02 ppm (m,4H), 4.48-4.55 ppm (q, 1H), 4.15-4.2 ppm (t, 4H), 4.0-4.04 ppm (q, 2H),3.88-3.96 ppm (m, 4H), 3.59-3.65 ppm (t, 4H), 3.47-3.54 ppm (m, 32H),2.95-3.1 ppm (m, 1H), 2.81-2.86 ppm (t, 4H), 2.67-2.70 ppm (t, 4H),2.62-2.68 ppm (m, 4H), 1.72-1.82 ppm (m, 4H), 1.1-1.15 ppm (t, 3H).

B. Synthesis of p(TE Diglycolate) Alternating

This synthesis generally followed the same steps as in section A of thisexample, except that step 2 used the same diacid as in the first step,namely diglycolic acid. Yield: 75%. Mol. Wt.: 47 kDa. Polydispersityindex (PDI): 1.25. Tg: 56.1° C.

NMR: 8.45 ppm (2H, NH, d), 8.3 ppm and 8.2 ppm (<0.1H, NH, doublets),7.3 ppm 7.1 ppm (8H, aromatic, a.sup.2b.sup.2), 4.45 ppm (2H, methinyl,m), 4.1 ppm (4H, diglycolate, q), 3.9 ppm (4H, O—CH₂, q), 3.1 ppm (4H,benzylic, m), 1.1 ppm (6H, terminal methyl, q/m).

C. Synthesis of p(TE Glutarate) Alternating

This synthesis generally followed the same steps as in section A of thisexample, except that in except that in step 1, the diacid was glutaricacid and in step 2, the same diacid was also used, namely glutaric acid.Yield: 61%. Mol. Wt.: 60 kDa, PDI: 1.24, Tg: 70° C.

NMR: 8.45 ppm 8.35 ppm (2H, NH doublets: 1:14), 7.3 ppm 7.1 ppm (total8H, aromatic, a.sup.2b.sup.2), 4.45 ppm (2H, methinyl, m), 4.1 ppm (4H,O—CH₂, m), 2.8 ppm (4H, terminal glutaryl, m), 2.7 ppm (4H, benzylic,m), 1.6 ppm (2H, central glutaryl, m), 1.1 ppm (6H, terminal methyl, t).

D. Synthesis of Polymers in Table 1

The synthesis for these polymers was generally done as described insection A of this example using the indicated aminophenol, timers anddiacids. Table 1 provides the molecular weights (determined by GPC) andthe Tg of many of these polymers.

Example 3 Synthesis of Random AP-X Polymers A. General Synthesis Route

The random polymers were generally synthesized as described in U.S. Pat.Nos. 5,216,115 and 5,597,507 using a carbodimide-mediated couplingreaction. Briefly, equimolar amounts of the aminophenol and the diacidwere condensed in methylene chloride using DIPC as the coupling agent inthe presence of 4-dimethylaminopyridium para-toluene sulfonic acid(DPTS). For polymers which contain a free acid moiety, a similarsynthesis was conducted by first synthesizing the corresponding benzylester containing polymer (i.e., the aminophenol had a benzyl ester)followed by hydrogenation as described in U.S. Pat. No. 6,120,491 toyield the free acid-containing polymer. The polymers were usuallyisolated by repeated precipitation from isopropanol.

B. Synthesis of p(TE Diglycolate) Random

The synthesis was as generally described in Section A of this example,using tyrosine ethyl ester as the aminophenol and diglycolic acid as thediacid. Yield: 60%. Mol. Wt. 27 kDa. PDI: 1.50. Tg: 54.5° C.

NMR: 8.45 ppm 8.35 ppm (2H, NH doublets: 1:1.6), 7.3 ppm 7.1 ppm (total8H, aromatic, a.sup.2b.sup.2), 4.45 ppm (2H, methinyl m), 4.1 ppm (4H,O—CH₂, m), 2.9 ppm (4H, terminal glutaryl, m), 2.7 ppm 2.4 ppm (4H,benzylic, m), 1.8 ppm (2H, central glutaryl, m), 1.1 ppm (6H, terminalmethyl, t).

C. Synthesis of p(TE Glutarate) Random

The synthesis was as generally described in Section A of this example,using tyrosine ethyl ester as the aminophenol and glutaric acid as thediacid. Mol. Wt.: 44 kDa; PDI: 1.19; Tg: 68° C.

D. Synthesis of p(TE Succinate) Random

The synthesis was as generally described in Section A of this example,using tyrosine ethyl ester as the aminophenol and succinic acid as thediacid.

Example 4 Polymer Degradation and Mass Loss Studies

For these studies, the indicated polymer and drug(s), if present, weredissolved in an organic solvent and spray coated onto a surgicalpolypropylene mesh. Typically, a 1% solution of polymer or of a ratio of1:1:8 rifampin:minocycline:polymer in 9:1 tetrahydrofuran/methanol isspray-coated onto a surgical mesh by repeatedly passing the spray nozzleover each side of the mesh until each side is coated with the desiredamount of antimicrobial-embedded polymer. Meshes are dried for at least72 hours in a vacuum oven before use and cut to size for degradationstudies.

Molecular weight (MW) profile: For monitoring MW decrease as a functionof time, meshes are incubated with 0.01 M PBS or 0.01M PBS with Tween20(50 to 100 mL) at 37° C. with shaking. At each time point, polymersamples are dissolved in solvent, filtered and transferred to analysisvials for analysis by gel permeation chromatography (GPC).

Mass loss profile: For mass loss analysis, meshes are incubated with0.01M PBS or 0.01M PBS with Tween 20 (50 to 100 mL) at 37° C. withshaking. The buffer in the vials is changed at periodic intervals andanalyzed for soluble degrading components. At each time point, 1-2 mLbuffer from three small vials are filtered and transferred to analysisvials for analysis by reversed phase HPLC. Alternately, the devices canbe washed, dried and weighed (final weight) and the mass loss determinedby subtracting the final weight from the original weight.

The results for mass retained under physiological degradation conditionsfor random and alternating polymers on polymer-coated meshes is shown inFIG. 1. The results for molecular weight retained under physiologicaldegradation conditions for random and alternating polymers is shown inFIG. 2 and, for three different random polymers is shown in FIG. 3.

Example 5 Drug Release Studies

Polymer films are made by dissolving sufficient polymer in 9:1tetrahydrofuran (THF) and methanol (MeOH) to yield a 10% (w/v) polymersolution. After the polymers are dissolved, rifampin and minocycline areadded to reach 3% of each drug in solution and mixed well. Polypropyleneor delrin molds in the shape of a breast implant are fixed onto a holderand dipped slowly into and slowly out of the solution using a dippingmachine from DipTech Systems, Inc with 10-60 min intervals between eachsuccessive dip. The dipped molds are dried at room temperature in a blowoven for 5 h followed by drying in a 50° C. oven for 16 h. After drying,the molded polymer produces a breast implant covering that is easilypeeled from the mold. This covering is further dried off mold at 50° C.for 72 h. Small discs or pieces are cut from these coverings and usedfor drug release studies.

Alternatively, the solution can be poured onto a TEFLON coated glasssurface and spread to 0.25 mm with a spreading knife. The film iscovered by an aluminum foil wrapped glass dish and dried at roomtemperature overnight. The film is peeled off and put in an amber bagand dried in a vacuum oven at 50° C. for 3 days. The dried film is cutinto small pieces of about 10 mg.

When coated meshes are used, the meshes are spray coated as described inExample 4, and after drying, are cut into pieces for drug releasestudies.

The discs, pieces or meshes are placed into a 20 mL vial containing 10mL of PBS. Aliquots of buffer are removed periodically for analysis andreplaced with fresh buffer. Samples are analyzed by HPLC to determinethe cumulative amount of released rifampin and/or minocycline.

The results in FIG. 4 show the cumulative percentage release of rifampinunder physiological conditions for four random polymers onpolymer-coated meshes: TE succinate; TE glutarate; TE diglycolate; andTE:15T glutarate.

Example 6 Comparative Molecular Weight and Mass Losses

Molecular weight is determined as described in Example 4 for p(DTEsuccinate) and a polymer of the invention, p(TE succinate) spray coatedon to polypropylene meshes. The molecular weight loss, expressed asmolecular weight retained, is shown in FIG. 5.

A comparative example of mass loss is provided in FIG. 6 in which themass loss under physiological conditions on spray-coated polypropylenemeshes is shown for two tyrosine-derived diphenol polyarylates—p(10%desaminotyrosyl tyrosine 90% desaminotyrosyl tyrosine ethyl estersuccinate) and p(15% desaminotyrosyl tyrosine 85%desaminotyrosyltyrosine ethyl ester succinate)—relative to a polymer ofthe invention-p(TE succinate).

1. A synthetic polymer comprising monomer units represented by the formula:

wherein R is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁ is hydrogen; saturated or unsaturated alkyl, aryl, alkylaryl or alkyl ether having from 1 to 20 carbon atoms; or —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆; each R₂ is independently a divalent, linear or branched, substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene, divalent alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or —(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—; R₃ and R₄ are each independently, hydrogen or linear or branched, substituted or unsubstituted alkyl having from 1 to 10 carbon atoms, R₅ is independently linear or branched lower alkylene or lower alkenylene; R₆ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated lower alkyl; the aromatic ring has from zero to four Z₁ substituents, each of which is independently selected from the group consisting of halide, lower alkyl, alkoxy, nitro, alkyl ether, a protected hydroxyl group, a protected amino group and a protected carboxylic acid group; Y is

a is 0, or 2 to 10; each q is independently 1 to 4; each r is independently 1 to 4; and each s is independently 1 to
 5000. 2. A synthetic polymer comprising monomer units represented by the formula:

wherein R is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁ is hydrogen; saturated or unsaturated alkyl, aryl, alkylaryl or alkyl ether having from 1 to 20 carbon atoms; or —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆; each R₂ is independently a divalent, linear or branched, substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene, divalent alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or —(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—; R₃ and R₄ are each independently, hydrogen or linear or branched, substituted or unsubstituted alkyl having from 1 to 10 carbon atoms, R₅ is independently linear or branched lower alkylene or lower alkenylene; R₆ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated lower alkyl; the aromatic ring has from zero to four Z₁ substituents, each of which is independently selected from the group consisting of halide, lower alkyl, alkoxy, nitro, alkyl ether, a protected hydroxyl group, a protected amino group and a protected carboxylic acid group; Y is

a is 0 to 10; each q is independently 1 to 4; each r is independently 1 to 4; and each s is independently 1 to
 5000. 3. A pharmaceutical composition comprising the polymer of claim 2 and one or more drugs.
 4. The pharmaceutical composition of claim 3, wherein said one or more drugs are selected from the group consisting of antimicrobial agents, antibacterial agents, anesthetics, anti-inflammatory agents, anti-scarring agents, anti-fibrotic agents, leukotriene inhibitors, chemotherapeutic agents.
 5. The pharmaceutical composition of claim 4, wherein said one or more drugs is an antimicrobial agent selected from the group consisting of rifampin, minocycline, gentamicin, vancomycin, triclosan, and combinations thereof.
 6. A synthetic polymer comprising monomer units represented by the formula:

wherein R is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁ is hydrogen; saturated or unsaturated alkyl, aryl, alkylaryl or alkyl ether having from 1 to 20 carbon atoms; or —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆; each R₂ is independently a divalent, linear or branched, substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene, divalent alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or —(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—; R₃ and R₄ are each independently, hydrogen or linear or branched, substituted or unsubstituted alkyl having from 1 to 10 carbon atoms, R₅ is independently linear or branched lower alkylene or lower alkenylene; R₆ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated lower alkyl; the aromatic ring has from zero to four Z₁ substituents, each of which is independently selected from the group consisting of halide, lower alkyl, alkoxy, nitro, alkyl ether, a protected hydroxyl group, a protected amino group and a protected carboxylic acid group; Y is

a is 0 to 10; each q is independently 1 to 4; each r is independently 1 to 4; each s is independently 1 to 5000; and wherein said repeat units are strictly alternating of the form (a)_(n). 